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Article
Liquefying Compounds by Forming Deep Eutectic
Solvents: A Case-Study for Organic Acids and Alcohols
Dinis O. Abranches, Renato O. Martins, Liliana Patrocínio Silva, Mónia
Andreia Rodrigues Martins, Simao P. Pinho, and Joao A.P. Coutinho
J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.0c02386 • Publication Date (Web): 23 Apr 2020
Downloaded from pubs.acs.org on April 24, 2020

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3
4 Liquefying Compounds by Forming Deep Eutectic Solvents: A
5
6 Case-Study for Organic Acids and Alcohols
7
8
9 Dinis O. Abranches1, Renato O. Martins1, Liliana P. Silva1, Mónia A. R. Martins1, Simão P.
10 Pinho2 and João A. P. Coutinho1,*
11
12
1CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro,
13
14 3810-193 Aveiro, Portugal
15
2Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança. Campus de
16
17 Santa Apolónia, 5300-253 Bragança, Portugal
18 *
19 Corresponding Author e-mail: jcoutinho@ua.pt
20
21
22
23 Abstract
24
25 The criterion to distinguish a simple eutectic mixture from a deep eutectic solvent (DES) lies
26
27 in the deviations to thermodynamic ideality presented by the components in the system. In this
28
29 work, the current knowledge of the molecular interactions in types III and V DES is explored
30
to liquefy a set of three fatty acids and three fatty alcohols, here used as model compounds for
31
32 carboxyl and hydroxyl containing solid compounds.
33
34
35
This work shows that thymol, a stronger than usual hydrogen bond donor, is able to form deep
36 eutectic solvents of type V with the fatty alcohols studied. This is particularly interesting since
37
38 these DES formed are hydrophobic. Regarding type III DES, the results suggest that the
39
40 prototypical DES hydrogen bond acceptor, cholinium chloride, is unable to induce negative
41
deviations to ideality in the model molecules studied. By substituting choline with
42
43 tetramethylammonium chloride it is shown that the choline hydroxyl group is responsible for
44
45 the difficulty in forming choline-based deep eutectic solvents and that its absence induces
46
47 strong negative deviations to ideality in the alkylammonium side. Finally, it is demonstrated
48 that tetrabutylammonium chloride acts as a chloride donning agent, causing significant
49
50 negative deviations to ideality in both fatty acids and alcohols, and leading to the formation of
51
52 deep eutectic solvents of type III.
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3 1. Introduction
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5
6 Deep eutectic solvents (DES) are a novel class of solvents1,2 that emerged from the seminal
7
works of Abbott and co-workers,2,3 where it was reported that binary mixtures of cholinium
8
9 chloride and urea or a series of carboxylic acids (malonic acid, phenylpropanoid acid or
10
11 phenylacetic acid) are liquid at room temperature. Putting it simply, and despite some
12
13 questionable exceptions also presented by Abbott et al.4,5 using liquid components, eutectic
14 solvents (ES) could be defined as liquid mixtures prepared from pure solid compounds. The
15
16 liquid phase of ES arises due to the melting point depression of the system, which depends on
17
18 the melting temperature and enthalpy of its components as well as their intermolecular
19
20
interactions. The greater the negative deviations to thermodynamic ideality of both
21 components, the greater the melting temperature depression, with the prefix deep here
22
23 attributed to systems showing negative deviations to ideality.6
24
25 Deep eutectic solvents have found applications in a variety of scientific areas, such as
26
27 extraction and separation,7–12 reaction chemistry,13–16 analytical chemistry,17 biodiesel
28
29 synthesis18,19 and electrochemistry.20 Interestingly, cholinium chloride-based DES are by far
30
31
the most studied in the literature,1–3,6–21 even though cholinium chloride typically displays a
32 thermodynamically ideal behavior in these systems.6,22 Its attractiveness as a DES component
33
34 stems from its low toxicity,23 high biodegradability24 and low melting enthalpy (4.3 kJ/mol),25
35
36 causing it to present a steep solid-liquid equilibrium line and, thus, a sharp melting temperature
37
depression effect.
38
39
40 The non-ideality of a liquid mixture arises from the establishment of intermolecular
41
42 interactions of different strength than the interactions the compounds establish with themselves
43 in their pure liquid phases. Since negative deviations to ideality are the basis for classifying an
44
45 ES as deep, our research group has been focused on understanding the interactions between
46
47 DES components, aiming at rationalizing the design of true deep eutectic solvents.
48
49 Recently we proposed a new type of DES (type V) based on non-ionic substances.26 Despite
50
51 the structural similarity of its components, the system thymol/menthol presents large negative
52
53 deviations to ideality and is an example of this new class of DES. Due to the electron
54 withdrawing effect of the aromatic resonance of thymol, its hydroxyl group becomes more
55
56 positive, with the oxygen becoming a poorer hydrogen bond acceptor and its proton becoming
57
58 a better hydrogen bond donor when compared with the hydrogen bonding capability of typical
59
60
alcohols (such as menthol). Hence, thymol and menthol establish a stronger hydrogen bond

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3 network than those present in the liquid phase of the pure components. We have also identified
4
5 mixtures in which tetrabutylammonium chloride ([N4,4,4,4]Cl) behaves as a chloride donning
6
7 agent,27 analogous to the mechanism of formation of type I DES. An example is the system
8
9
[N1,1,1,1]Cl/[N4,4,4,4]Cl with [N1,1,1,1]Cl standing for tetramethylammonium chloride, which
10 presents large negative deviations to ideality27 due to a synergetic share of the available
11
12 chloride ions, in which the coordination number of chloride anions around the [N1,1,1,1]+ cation
13
14 increases (when compared to its pure liquid phase) and decreases around the [N4,4,4,4]+ cation
15
(in comparison to its pure liquid phase). This phenomenon, as will be shown here, can be
16
17 explored to design novel type III deep eutectic solvents.
18
19
20
The objective of this work is to show that the current understanding of the molecular
21 mechanisms behind DES formation, with emphasis on DES of types III and V, allows for an
22
23 informed choice of liquefying agents, i.e. compounds that induce negative deviations to ideality
24
25 in other solid compounds, originating a liquid mixture. Fatty acids (and carboxylic acids in
26
general) are both hydrogen bond donors and acceptors, with the possibility of forming dimers
27
28 in their pure liquid phases. Likewise, fatty alcohols are also both good hydrogen bond donors
29
30 and acceptors. Their simple structure, minimizing the possibility of other specific interactions
31
32 that could create difficulties in the interpretation of the results, and their melting points above
33 room temperature, makes them attractive model compounds for this study.
34
35
36 In this work, a set of experimental solid-liquid equilibrium data taken from the literature,
37
complemented with new data herein measured, is used to rationalize the liquefaction of fatty
38
39 acids or alcohols using the deep eutectic solvent approach. Fatty acids (tetradecanoic acid,
40
41 hexadecanoic acid and octadecanoic acid) and fatty alcohols (tetradecan-1-ol, hexadecan-1-ol
42
43 and octadecan-1-ol) are here used as model compounds to be liquefied and menthol, thymol,
44 cholinium chloride (ChCl), [N1,1,1,1]Cl or [N4,4,4,4]Cl as compounds to induce the liquefaction.
45
46 The identification of the dominant molecular interactions present on these systems will help
47
48 understand the behavior of a plethora of other systems, and will pave the way to the design of
49
50
novel DES that are not just ideal mixtures of compounds forming, in some cases, eutectic
51 solvents.
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3 2. Methods
4
5
6 2.1 Chemicals
7
8 The substances experimentally used in this work are reported in Table 1, along with their
9
10 supplier and purity (mass %). Due to their hygroscopicity, [N1,1,1,1]Cl and [N4,4,4,4]Cl were dried
11
12 before use by stirring in vacuum (0.1 Pa) at room temperature (298 K), for at least 72 hours.
13 The remaining compounds were used as received. The water content of the substances was
14
15 measured using a Metrohm 831 Karl Fischer coulometer, with the analyte Hydranal Coulomat
16
17 AG from Riedel-de-Haen.
18
19 Table 1. List of substances experimentally used in this work along with their CAS number,
20
supplier, mass purity and water content.
21
22 Substance CAS Number Supplier Purity Water Content /ppm
23 [N1,1,1,1]Cl 75-57-0 Sigma-Aldrich 97 % 2957
24
25 [N4,4,4,4]Cl 1112-67-0 Sigma-Aldrich 97 % 5758
26 Thymol 89-83-8 TCI >99 % 185
27
28 (-)-Menthol 2216-51-5 Acros Organics 99.5 % 79
29 Tetradecanoic Acid 544-63-8 Acros Organics 99 % 0
30
Hexadecanoic Acid 57-10-3 Aldrich 99 % 13
31
32 Octadecanoic Acid 57-11-4 Sigma-Aldrich 99 % 12
33 Tetradecan-1-ol 112-72-1 Alfa Aesar 98 % 66
34
35 Hexadecan-1-ol 36653-82-4 Alfa Aesar 98 % 6
36 Octadecan-1-ol 112-92-5 Sigma 99 % 18
37
38
39
40 2.2 Solid-Liquid Phase Diagram Measurement
41
42 To study liquefaction by forming type V DES, the solid-liquid equilibrium (SLE) phase
43
44 diagram of the binary systems composed of thymol or (-)-menthol (menthol) and
45
46 tetradecan-1-ol (tetradecanol), hexadecan-1-ol (hexadecanol) or octadecan-1-ol (octadecanol)
47 were experimentally measured. Moreover, to study liquefaction by forming type III DES, the
48
49 SLE phase diagram of the binary systems composed of [N1,1,1,1]Cl and tetradecanol,
50
51 hexadecanol or octadecanol, and composed of [N4,4,4,4]Cl and tetradecanoic acid, hexadecanoic
52
53
acid, octadecanoic acid, tetradecanol, hexadecanol or octadecanol were also measured in this
54 work.
55
56
57 For each binary system, mixtures were prepared covering the entire composition range. The
58 mass of each component was weighted using an analytical balance (model ALS 220-4N from
59
60 Kern) with a readability of 0.1 mg. After preparation, the samples were heated under stirring

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3 until fusion and recrystallized to obtain a homogeneous solid mixture. Then, the samples were
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5 crushed with a mortar and pestle and glass capillaries were filled with the resulting powder.
6
7 The melting temperature of the sample in each glass capillary, taken as the temperature at which
8
9
complete fusion is observed, was measured using the melting point device model M-565 from
10 Büchi, with a temperature resolution of 0.1 K and a temperature gradient of 0.1 K/min. This
11
12 procedure was repeated at least three times. For systems composed of either [N1,1,1,1]Cl or
13
14 [N4,4,4,4]Cl, the sample and capillary preparation were performed inside a dry-argon glove box
15
to prevent atmospheric humidity contamination.
16
17
18 In the cases where the melting temperature of the mixture was below room temperature, the
19
20
recrystallization technique was not possible. Thus, approximately 5 mg of these samples
21 weighed using a micro-analytical balance AD6 (PerkinElmer, USA, precision = 2 × 10−6 g),
22
23 were tightly sealed in aluminum pans and their melting temperature measured using differential
24
25 scanning calorimetry (DSC). A Hitachi DSC7000X model, working at atmospheric pressure,
26
coupled with a cooling system, was used to perform the measurements. The cooling and heating
27
28 rates were respectively 5 K/min and 2 K/min and each temperature was taken as the peak
29
30 temperature upon heating. The DSC equipment was previously calibrated with several
31
32 standards (heptane, octane, decane, 4-nitrotoluene, naphthalene, benzoic acid, diphenylacetic
33 acid, indium, tin, caffeine, lead, zinc, potassium nitrate, water, and anthracene) with purities
34
35 higher than 99 wt%.
36
37
The experimental methodologies described above have already been checked for the SLE phase
38
39 diagram measurement of DES by comparing the measured data with other sources and
40
41 methods28,29 as well as applying thermodynamic consistency tests.25 The foundations of these
42
43 methodologies are extensively described by Hefter and Tomkins.30
44
45 2.3 Modelling
46
47
Solid-liquid equilibrium,31–33 when no solid-solid transitions are present, the components
48
49 crystalize as pure substances, assuming also constant heat capacity change upon melting, and
50
51 neglecting the difference between melting and triple point properties, is described by:
52
53 ∆𝑚ℎ𝑖 ∆𝑚𝐶𝑃,𝑖 𝑇𝑚,𝑖 𝑇𝑚,𝑖
54 ln (𝑥𝑖 ∙ 𝛾𝑖) = 𝑅 ∙ ( 1
𝑇𝑚,𝑖
1
―𝑇 + ) 𝑅 ∙ ( 𝑇 ― 𝑙𝑛 𝑇 )
―1 (1)
55
56
57 where 𝑥𝑖 is the mole fraction of component 𝑖, 𝛾𝑖 is its activity coefficient in the liquid phase, ∆𝑚
58
ℎ𝑖 is its melting enthalpy, 𝑇𝑚,𝑖 is its melting temperature, ∆𝑚𝐶𝑃,𝑖 is its heat capacity change
59
60 upon melting, 𝑅 is the ideal gas constant and 𝑇 is the absolute temperature of the system. Given
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3 the small temperature difference between the melting temperature of the mixtures herein
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5 studied and those of the pure compounds the heat capacity term is negligible,31,32 with
6
7 Equation 1 simplifying to:
8
9 ∆𝑚ℎ𝑖
10 ln (𝑥𝑖 ∙ 𝛾𝑖) = 𝑅 ∙ ( 1
𝑇𝑚,𝑖
1
―𝑇 ) (2)
11
12
13
The activity coefficients of the components in a eutectic solvent can be calculated from the
14 experimental solid-liquid phase diagram by rearranging Equation 2:
15
16
[ ∙( )]
∆𝑚ℎ𝑖 1 1
17 𝑒𝑥𝑝 𝑅 𝑇𝑚,𝑖 ―𝑇
18 𝛾𝑖 = (3)
𝑥𝑖
19
20
21 In this work, the activity coefficients were calculated using Equation 3 and the melting
22
23 properties listed in Table S1. Even for the cases where the activity coefficients were already
24 reported in the literature, they were herein recalculated using the melting properties of Table S1
25
26 to perform consistent comparisons between all systems.
27
28
29
30
31 3. Discussion
32
33 3.1 Liquefying acids and alcohols by forming type V DES
34
35
36 Due to the non-ionic nature of type V DES, the interactions established between their
37 components are simpler to understand and discuss, and our analysis starts with these systems.
38
39 The solid-liquid phase diagram of menthol and the model fatty acids, taken from the
40
41 literature,34 are depicted in Figure 1, along with the corresponding activity coefficients
42
43
estimated from Eq. (3) as described in section 2.3.
44
45
46
47
48
49
50
51
52
53
54
55
56
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3 350
4 (a)
5 340
6
7 330
8
T /K

9 320
10
11 310
12
13 300
14
15 290
16 0.0 0.1 0.2 0.3 0.4 0.5
xMenthol 0.6 0.7 0.8 0.9 1.0
17 2.0 2.0
18 (b) (c)
19 1.6 1.6
20
21
1.2 1.2
22 ϒMenthol
ϒAcid

23
24 0.8 0.8
25
26 0.4 0.4
27
28 0.0 0.0
29 0.0 0.2 0.4
xMenthol
0.6 0.8 0.8 0.9
xMenthol
1.0
30
31 Figure 1. Solid-liquid phase diagrams34 (a) and corresponding activity coefficients of fatty
32
33 acids (b) and menthol (c), for the systems composed of menthol and tetradecanoic acid (◆),
34 hexadecanoic acid (◆) or octadecanoic acid (◆). Dashed lines represent the ideal liquidus
35 lines (- - - menthol, - - - tetradecanoic acid, - - - hexadecanoic acid and - - - octadecanoic acid).
36
37 Dotted lines represent thermodynamic ideality (ϒ=1).
38
39 Figure 1 shows that both fatty acids and menthol behave ideally when mixed, with only mild
40
41 deviations to ideality presented by the acids for high menthol concentration. Therefore, the
42
43
molecular interactions established in the mixture are similar and of the same strength to those
44 present in the pure component liquid phases (hydrogen bonding between hydroxyl groups of
45
46 similar nature). As such, and even though the system menthol/tetradecanoic acid presents a
47
48 eutectic temperature around room temperature (ca. 296 K), menthol fails at forming deep
49
eutectic solvents with the organic acids studied.
50
51
52 The solid-liquid phase diagram of menthol and the model fatty alcohols were measured in this
53
54
work, as described in section 2.2, and are depicted in Figure 2, along with the corresponding
55 activity coefficients.
56
57
58
59
60

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2
3 335
4 (a)
330
5
6 325
7 320
8 315
T /K

9
310
10
11 305
12 300
13
295
14
15 290
16 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
xMenthol
17 2.0 2.0
18 (b) (c)
19 1.6 1.6
20
21
1.2 1.2
22 ϒMenthol
ϒAlcohol

23
24 0.8 0.8
25
26 0.4 0.4
27
28 0.0 0.0
29 0.0 0.2 0.4
xMenthol
0.6 0.8 0.7 0.8
xMenthol
0.9 1.0
30
31 Figure 2. Solid-liquid phase diagrams (a) and corresponding activity coefficients of fatty
32
33 alcohols (b) and menthol (c), for the systems composed of menthol and tetradecanol (●),
34 hexadecanol (●) or octadecanol (●). Dashed lines represent the ideal liquidus lines (- - -
35 menthol, - - - tetradecanol, - - - hexadecanol and - - - octadecanol). Dotted lines represent
36
37 thermodynamic ideality (ϒ=1).
38
39 Similar to the menthol/fatty acid systems depicted in Figure 1, Figure 2 reveals that mixtures
40
41 of menthol and fatty alcohols behave ideally. Again, the molecular interactions between
42
43
menthol and the fatty alcohols present in these systems are comparable in strength to those
44 found in the liquid phases of the pure components.
45
46
47 The results reported in Figures 1 and 2 reassert that the existence of hydrogen bonds between
48 the two components of a mixture does not guarantee the presence of negative deviations to
49
50 ideality and, thus, the formation of deep eutectic solvents. For this to happen, the interactions
51
52 established between the components must be stronger than those present in the pure compound
53
54
liquid phases. Within the framework of type V DES, these results show that aliphatic alcohols
55 such as menthol, being hydrogen bond donors and acceptors of average strength able to
56
57 establish strong interactions with themselves in their pure liquid phases, are not useful to
58
59 liquefy other substances with hydroxyl and/or carboxyl groups by causing deviations to
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3 thermodynamic ideality. This conclusion is in line to our previous work, where it was shown
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5 that menthol was not responsible for the significant negative deviations to ideality present in
6
7 the thymol/menthol system.26 It is also in good agreement, and helps explaining, previous
8
9
reports of SLE phase diagrams of menthol forming ideal liquid mixtures with various other
10 compounds34–39.
11
12
13 Having discussed the effect of menthol on organic acids and alcohols, the focus now shifts to
14 thymol (see Figure S2 for both structures). Unlike menthol, thymol has a hydrogen bond
15
16 capability unbalance: it is a stronger hydrogen bond donor and a weaker hydrogen bond
17
18 acceptor than other hydroxyl-containing non-phenolic compounds.26 The solid-liquid phase
19
20
diagram of thymol and the model fatty acids, taken from the literature,34 are depicted in
21 Figure 3, along with the corresponding activity coefficients.
22
23 350
24 (a)
25
26 340
27
28 330
29
T /K

30
320
31
32
33 310
34
35 300
36 0.0 0.1 0.2 0.3 0.4 0.5
xThymol 0.6 0.7 0.8 0.9 1.0
37
2.0 2.0
38 (b) (c)
39
40 1.6 1.6
41
42 1.2 1.2
ϒThymol
ϒAcid

43
44 0.8 0.8
45
46 0.4 0.4
47
48 0.0 0.0
49 0.0 0.2 0.4 0.6 0.8 0.6 0.7 0.8 0.9 1.0
50 xThymol xThymol
51
52 Figure 3. Solid-liquid phase diagrams34 (a) and corresponding activity coefficients of fatty
53 acids (b) and thymol (c), for the systems composed of thymol and tetradecanoic acid (◆),
54 hexadecanoic acid (◆) or octadecanoic acid (◆). Dashed lines represent the ideal liquidus
55
56 lines (- - - thymol, - - - tetradecanoic acid, - - - hexadecanoic acid and - - - octadecanoic acid ).
57 Dotted lines represent thermodynamic ideality (ϒ=1).
58
59
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3 Despite its hydrogen bond donning strength, Figure 3 shows that thymol cannot induce
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5 negative deviations to ideality in the model fatty acids and, thus, cannot form deep eutectic
6
7 solvents with these substances. In fact, and unlike menthol/acid systems, the fatty acids studied
8
9
present small positive deviations to ideality for high thymol concentration. Since the principal
10 structural difference between thymol and menthol is that the former is a stronger hydrogen
11
12 bond donor and a weaker hydrogen bond acceptor, the different activity coefficient results from
13
14 Figures 1b and 3b suggest that fatty acids are acting as the hydrogen bond donors and
15
thymol/menthol as the hydrogen bond acceptors. Menthol being a better hydrogen bond
16
17 acceptor than thymol26 induces the small negative deviations seen in Figure 1b.
18
19
20
The solid-liquid phase diagram of thymol with the model fatty alcohols were measured in this
21 work, as described in section 2.2, and are depicted in Figure 4, together with the corresponding
22
23 activity coefficients.
24
25 340
26 (a)
27 330
28
29 320
30
T /K

31 310
32
33 300
34
35 290
36
37 280
38 0.0 0.1 0.2 0.3 0.4 0.5
xThymol 0.6 0.7 0.8 0.9 1.0
39 2.0 2.0
40 (b) (c)
41 1.6 1.6
42
43
1.2 1.2
44
ϒAlcohol

ϒThymol

45
46 0.8 0.8
47
48 0.4 0.4
49
50 0.0 0.0
51 0.0 0.2 0.4
xThymol 0.6 0.8 0.5 0.7 xThymol 0.9
52
53 Figure 4. Solid-liquid phase diagrams (a) and corresponding activity coefficients of fatty
54
55 alcohols (b) and thymol (c), for the systems composed of thymol and tetradecanol (●),
56 hexadecanol (●) or octadecanol (●). Dashed lines represent the ideal liquidus lines (- - -
57 thymol, - - - tetradecanol, - - - hexadecanol and - - - for octadecanol). Dotted lines represent
58
59 thermodynamic ideality (ϒ=1).
60

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3 The phase diagrams depicted in Figure 4 demonstrate the usefulness of thymol as a liquefying
4
5 agent by forming DES of type V. Because thymol is a stronger hydrogen bond donor than the
6
7 fatty alcohols it can induce large deviations to ideality on the aliphatic alcohols by forming
8
9
hydrogen bonds that are stronger than those present in the pure compounds, as also shown in a
10 previous work for the mixture thymol-menthol,26 leading to deep eutectic solvents of type V.
11
12 Hydrophobic deep eutectic solvents, proposed for the first time by van Osch et al.,40 expand
13
14 the applicability of DES since most previously reported in the literature are choline-based,
15
hence hydrophilic. In this respect, the new DES reported in Figure 4 are important since they
16
17 are formed by hydrophobic substances, echoing the importance of type V DES, and the
18
19 informed selection of the compounds of the eutectic solvent mixture, in the preparation of novel
20
21 hydrophobic solvents.
22
23 3.2 Liquefying alcohols and acids by forming type III DES
24
25 After showing how the type V DES framework can be used in the liquefaction of organic
26
27 alcohols, yet failing, with the liquefying agents studied, at forming deep eutectic solvents with
28
29 the fatty acids, type III DES are now discussed. We start by analyzing the prototypical DES-
30
31
forming component: cholinium chloride. It has been previously proposed that the
32 thermodynamic behavior of the prototypical cholinium chloride/urea DES is governed by a
33
34 hydrogen bond between two protons of urea and a chloride anion,41 which is a behavior
35
36 reminiscent of the chloride transfer in the type I DES-analogous ionic liquid mixtures
37
mentioned in the introduction section.27
38
39
40 To investigate if cholinium chloride is able to form DES with fatty acids, Figure 5 depicts their
41
42 binary solid-liquid phase diagrams,28 and the corresponding activity coefficients.
43
44
45
46
47
48
49
50
51
52
53
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55
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1
2
3 600
4 (a)
5 550
6
7 500
8
T /K

9 450
10
11 400
12
13 350
14
15 300
16 0.0 0.1 0.2 0.3 0.4 x0.5 0.6 0.7 0.8 0.9 1.0
ChCl
17 2.0 2.0
18 (b) (c)
19 1.6 1.6
20
21
1.2 1.2
22
ϒAcid

ϒChCl
23
24 0.8 0.8
25
26 0.4 0.4
27
28 0.0 0.0
29 0.0 0.2
xChCl 0.4 0.4 0.6 xChCl 0.8 1.0
30
31 Figure 5. Solid-liquid phase diagrams28 (a) and corresponding activity coefficients of fatty
32 acids (b) and ChCl (c), for the systems composed of ChCl and tetradecanoic acid (◆),
33
34 hexadecanoic acid (◆) or octadecanoic acid (◆). Dashed lines represent the ideal liquidus
35 lines (- - - ChCl, - - - tetradecanoic acid, - - - hexadecanoic acid and - - - octadecanoic acid).
36 Dotted lines represent thermodynamic ideality (ϒ=1).
37
38
39 Excluding the ChCl/tetradecanoic acid system in which cholinium chloride behaves ideally,
40
Figure 5 reveals that both cholinium chloride and fatty acids present significant positive
41
42 deviations to ideality when mixed. To investigate if, unlike the ChCl/acid systems, cholinium
43
44 chloride is able to form DES with fatty alcohols, Figure 6 depicts the solid-liquid phase
45
46 diagrams of these systems, taken from the literature,28 along with the corresponding activity
47 coefficients.
48
49
50
51
52
53
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55
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2
3 640
4 (a)
5 590
6
540
7
8 490
T /K

9
10 440
11
390
12
13 340
14
15 290
16 0.0 0.1 0.2 0.3 0.4 x0.5 0.6 0.7 0.8 0.9 1.0
ChCl
17 2.0 2.0
18 (b) (c)
19 1.6 1.6
20
21
1.2 1.2
22
ϒAlcohol

ϒChCl
23
24 0.8 0.8
25
26 0.4 0.4
27
28 0.0 0.0
29 0.0 0.2 xChCl 0.4 0.6 0.5 0.7 xChCl 0.9
30
31 Figure 6. Solid-liquid phase diagrams28 (a) and corresponding activity coefficients of fatty
32
33 alcohols (b) and ChCl (c), for the systems composed of ChCl and tetradecanol (●),
34 hexadecanol (●) or octadecanol (●). Dashed lines represent the ideal liquidus lines (- - - ChCl,
35 - - - tetradecanol, - - - hexadecanol and - - - octadecan-1-ol). Dotted lines represent
36
37 thermodynamic ideality (ϒ=1).
38
39 The results reported in Figure 6 are similar to those shown in Figure 5, with the fatty alcohols
40
41 presenting large positive deviations to ideality. However, cholinium chloride now shows either
42
43
an ideal behavior or small negative deviations to ideality. These results confirm that cholinium
44 chloride does not present a particular ability to establish new, and stronger than in pure,
45
46 intermolecular interactions in mixtures.
47
48 Since these results show that cholinium chloride cannot form deep eutectic solvents with the
49
50 fatty acids or alcohols studied, [N1,1,1,1]Cl will be now considered. This is an interesting
51
52 compound to discuss since it is structurally similar to cholinium chloride, with the sole
53
54
difference being the hydroxyethyl group of the cholinium cation replaced by a methyl group.
55 Thus, by studying [N1,1,1,1]Cl-based systems the effect of the choline hydroxyl group can be
56
57 probed whilst checking for DES formation by charge transfer. Figure 7 depicts the solid-liquid
58
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3 phase diagrams of [N1,1,1,1]Cl and the model fatty acids, taken from the literature,29 along with
4
5 the corresponding activity coefficients.
6
7 650
8 (a)
9 600
10
550
11
12 500
T /K

13
14 450
15
16 400
17 350
18
19 300
20 0.0 0.1 0.2 0.3 0.4 0.5
x[N1,1,1,1]Cl 0.6 0.7 0.8 0.9 1.0
21 2.0 2.0
22 (b) (c)
23
1.6 1.6
24
25
ϒ[N1,1,1,1]Cl

26 1.2 1.2
ϒAcid

27
28 0.8 0.8
29
30 0.4 0.4
31
32 0.0 0.0
33 0.0 0.2 0.4 0.4 0.6 0.8 1.0
x[N1,1,1,1]Cl x[N1,1,1,1]Cl
34
35
Figure 7. Solid-liquid phase diagrams29 (a) and corresponding activity coefficients of fatty
36
37 acids (b) and [N1,1,1,1]Cl (c), for the systems composed of [N1,1,1,1]Cl and tetradecanoic acid
38 (◆), hexadecanoic acid (◆) or octadecanoic acid (◆). Dashed lines represent the ideal
39
liquidus lines (- - - [N1,1,1,1]Cl, - - - tetradecanoic acid, - - - hexadecanoic acid and - - -
40
41 octadecanoic acid). Dotted lines represent thermodynamic ideality (ϒ=1).
42
43 The impact of the hydroxyl group present in cholinium chloride is quite significant, as the
44
45 comparison of Figures 5 and 7 reveal. While cholinium chloride presented large positive
46
47 deviations to ideality when mixed with the model acids, [N1,1,1,1]Cl presents the opposite
48 behavior, i.e. large negative deviations to ideality. Despite this change in behavior of the
49
50 liquefying agent, the model fatty acids still show positive deviations to ideality identical to
51
52 those found in the ChCl-based systems. This suggests that the hydroxyl group endows
53
54
cholinium chloride with stronger interactions in its pure phase, namely hydrogen bonding
55 between the chloride anion and the highly positive hydroxyl group. By removing this effect in
56
57 [N1,1,1,1]Cl, the hydrogen bonding with the fatty acids becomes more favorable than its
58
59 interactions in the pure liquid phase, resulting in the negative deviations seen.
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2
3 To check if the absence of hydroxyl group in [N1,1,1,1]Cl also affects the fatty alcohol systems,
4
5 Figure 8 depicts the solid-liquid phase equilibrium of [N1,1,1,1]Cl and the fatty alcohols, along
6
7 with the corresponding activity coefficients.
8
9 640
10 (a)
590
11
12 540
13
14 490
T /K

15
440
16
17 390
18
19 340
20
21 290
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
22 x[N1,1,1,1]Cl
23 2.0
24 2.8 (b) (c)
25 2.4 1.6
26
27 2.0
ϒ[N1,1,1,1]Cl

1.2
ϒAlcohol

28 1.6
29
1.2 0.8
30
31 0.8
32 0.4
0.4
33
34 0.0 0.0
35 0.0 0.2 0.4 0.4 0.5 0.6 0.7 0.8 0.9 1.0
x[N1,1,1,1]Cl x[N1,1,1,1]Cl
36
37 Figure 8. Solid-liquid phase diagrams (a) and corresponding activity coefficients of fatty
38
39
alcohols (b) and [N1,1,1,1]Cl (c), for the systems composed of [N1,1,1,1]Cl and tetradecanol (●),
40 hexadecanol (●) or octadecanol (●). Dashed lines represent the ideal liquidus lines (- - -
41 [N1,1,1,1]Cl, - - - tetradecanol, - - - hexadecanol and - - - octadecanol). Dotted lines represent
42
43
thermodynamic ideality (ϒ=1).
44
45 As observed for the systems of [N1,1,1,1]Cl and fatty acids, the absence of a hydroxyl group in
46
47 the tetramethylammonium cation results in very large deviations to ideality. Working under
48 the assumption that the chloride anion is a stronger hydrogen bond acceptor than the hydroxyl
49
50 groups of the fatty acids and alcohols studied (this will be later proven using [N4,4,4,4]Cl),
51
52 COOH--Cl or COH--Cl interactions should lead to negative deviations to ideality presented by
53
54
the acids/alcohols. On the contrary, the acids/alcohols in these systems show positive
55 deviations to ideality suggesting that COOH--Cl or COH--Cl interactions are not occurring.
56
57
58 Having seen that cholinium chloride is unable to form deep eutectic solvents with the model
59 acids and alcohols studied due to its hydroxyl group and that [N1,1,1,1]Cl produces highly
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2
3 asymmetrical systems with regards to activity coefficients, [N4,4,4,4]Cl is now discussed.
4
5 [N4,4,4,4]Cl has been shown to behave as a chloride donating agent, with its cation being able to
6
7 form apolar domains depleted in chloride anions.27 In this work, the solid-liquid phase diagrams
8
9
of the systems composed by [N4,4,4,4]Cl and the model fatty acids were measured and are
10 depicted in Figure 9.
11
12 360
13 (a)
14 350
15 340
16
17 330
18
T /K

320
19
20 310
21 300
22
290
23
24 280
25 0.0 0.1 0.2 0.3 0.4 0.5
x[N4,4,4,4]Cl 0.6 0.7 0.8 0.9 1.0
26
2.0 2.0
27 (b) (c)
28
29 1.6 1.6
30
ϒ[N4,4,4,4]Cl

31 1.2 1.2
ϒAcid

32
33 0.8 0.8
34
35 0.4 0.4
36
37
0.0 0.0
38 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.5 0.7 0.9
39 x[N4,4,4,4]Cl x[N4,4,4,4]Cl

40
41 Figure 9. Solid-liquid phase diagrams (a) and corresponding activity coefficients of fatty acids
42 (b) and [N4,4,4,4]Cl (c), for the systems composed of [N4,4,4,4]Cl and tetradecanoic acid (◆),
43 hexadecanoic acid (◆) or octadecanoic acid (◆). Dashed lines represent the ideal liquidus
44
45 lines (- - - [N4,4,4,4]Cl, - - - tetradecanoic acid, - - - hexadecanoic acid and - - - octadecanoic
46 acid). Dotted lines represent thermodynamic ideality (ϒ=1).
47
48 The results reported in Figure 9 are extremely interesting. On the contrary to what was observed
49
50 for all systems previously discussed, for the first time negative deviations to ideality are present
51
52 in the carboxylic acids. The [N4,4,4,4]Cl, however, presents either a near-ideal behavior or even
53
54
weak positive deviations to ideality. This behavior is reminiscent of that previously observed
55 in the [N1,1,1,1]Cl/[N4,4,4,4]Cl system,27 supporting the idea that chloride anions are being
56
57 transferred from the [N4,4,4,4] cation to the carboxylic acid head, engaging in stronger hydrogen
58
59 bonds than those present in the pure acid liquid phases.
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2
3 Bearing in mind the success of [N4,4,4,4]Cl in inducing negative deviations to ideality in the
4
5 model acids studied, the alcohol-based systems are now analyzed. The solid-liquid phase
6
7 diagrams of these systems were measured in this work and are depicted in Figure 10, along
8
9
with the corresponding activity coefficients. As can be seen, the behavior of [N4,4,4,4]Cl mixed
10 with fatty alcohols is quite similar to that observed with fatty acids. Again, [N4,4,4,4]Cl is able
11
12 to induce negative deviations to ideality in the alcohols, while retaining a near-ideal behavior
13
14 or showing weak positive deviations to ideality.
15
16 350
17
(a)
340
18
19 330
20
21 320
T /K

22
310
23
24 300
25
26 290
27
280
28
0.0 0.1 0.2 0.3 0.4 0.5
x[N4,4,4,4]Cl 0.6 0.7 0.8 0.9 1.0
29
30 2.0 2.0
31 (b) (c)
32 1.6 1.6
33
34 1.2 1.2
ϒAlcohol

35
ϒ

36 0.8
37 0.8
38
0.4
39 0.4
40
41 0.0
0.0 0.2 0.4 0.0
42 x[N4,4,4,4]Cl 0.4 0.6 xThymol 0.8 1.0
43
44 Figure 10. Solid-liquid phase diagrams (a) and corresponding activity coefficients of fatty
45
alcohols (b) and [N4,4,4,4]Cl (c), for the systems composed of [N4,4,4,4]Cl and tetradecanol (●),
46
47 hexadecanol (●) or octadecanol (●). Dashed lines represent the ideal liquidus lines (- - -
48 [N4,4,4,4]Cl, - - - tetradecanol, - - - hexadecanol and - - - octadecan-1-ol). Dotted lines represent
49
thermodynamic ideality (ϒ=1).
50
51
The thermodynamic behavior of the [N4,4,4,4]Cl-based systems and the [N1,1,1,1]Cl-based
52
53 systems is essentially opposite. [N1,1,1,1]Cl formed highly asymmetrical deep eutectic solvents
54
55 with the model fatty acids/alcohols studied, presenting severe negative deviations to ideality
56
57 itself but failing to induce them in the other component. Contrary to this behavior, [N4,4,4,4]Cl
58 induces strong negative deviations to ideality in the organic molecules but shows itself weak
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3 positive deviations to ideality. Such a drastic difference in thermodynamic behavior suggests
4
5 that the molecular interactions are fundamentally different in those two sets of systems.
6
7
Based on the results of our previous work,27 given the weak interaction between the cation and
8
9 anion in [N4,4,4,4]Cl, it is expected that this compound donates chloride anions to the organic
10
11 acids and alcohols, establishing hydrogen bonds that are stronger than those present in the
12
13 acids/alcohols pure liquid phases. Since the cation of [N1,1,1,1]Cl is much more densely charged,
14 it is unable to similarly donate chloride anions, functioning as the receiving end of chloride
15
16 anions in the [N1,1,1,1]Cl/[N4,4,4,4]Cl system as previously shown.27 Considering that [N1,1,1,1]Cl
17
18 shows severe negative deviations to ideality and considering that the acids and alcohols
19
20
presented severe positive deviations to ideality (which indicates that the new interactions
21 established in the mixture are weaker than those present in their pure liquid phase), it is
22
23 concluded that the cation of [N1,1,1,1]Cl is interacting with the negative zones of the organic
24
25 molecules (lone pairs of the oxygen atoms), further stabilizing itself by withdrawing additional
26
negative charge but preventing the hydrogen bonding between the organic molecules, leading
27
28 to the asymmetrical deviations to ideality seen in these systems.
29
30
31
32
33 4. Conclusions
34
35 Throughout this work, the feasibility of forming deep eutectic solvents based on fatty alcohols
36
37 or acids was studied using different liquefying agents. This work reiterates the importance of
38
39 studying the solid-liquid phase diagrams of deep eutectic solvents in order to understand their
40
41
molecular interactions, the origin of their deviations to ideality and rationalizing the search for
42 new DES.
43
44
45 Regarding type V DES, it was shown that thymol induces negative deviations to ideality in
46 organic alcohols, allowing the design of new hydrophobic deep eutectic solvents. Furthermore,
47
48 it was shown that menthol forms ideal mixtures with the fatty acids or alcohols studied, as
49
50 expected due to the similarity of the interactions established in these mixtures to those
51
52
established in the pure components liquid phases, confirming that the existence of hydrogen
53 bonding networks in eutectic solvents does not guarantee negative deviations to ideality and,
54
55 thus, does not mean that the eutectic solvent is deep.
56
57 In terms of type III DES, it was shown that cholinium chloride is unable to form deep eutectic
58
59 solvents with either fatty acids or alcohols. Using [N1,1,1,1]Cl, it was shown that the ideal
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3 behavior of cholinium chloride in the systems studied stems from its hydroxyethyl group,
4
5 which allows for strong cation-anion interactions in its pure, hypothetical, liquid phase. Thus,
6
7 although due to its low melting enthalpy and green properties, cholinium chloride can be seen
8
9
as a generic eutectic solvent-forming compound, it is however unable to form deep eutectic
10 solvents with organic acids or alcohols. Finally, it was shown that [N4,4,4,4]Cl forms deep
11
12 eutectic solvents with the fatty acids and alcohols studied.
13
14 Within the liquefying-agent concept, this work demonstrates the usefulness of thymol (type V
15
16 DES) and [N4,4,4,4]Cl (type III DES) in forming deep eutectic solvents with organic acids and
17
18 alcohols, leading to the liquefaction of these substances. More specifically, liquid mixtures
19
20
below room temperature (298 K) were obtained for tetradecanol when mixed with either
21 thymol or [N4,4,4,4]Cl, and for tetradecanoic and hexadecanoic acids when mixed with
22
23 [N4,4,4,4]Cl.
24
25 An understanding of the interactions between liquefying agents and organic substances allows
26
27 for the design of novel DES of importance to green chemistry. This work highlights some of
28
29 these interactions and liquefying agents that can induce them, but further investigation is still
30
31
required to compile a full body of these favorable interactions for classes of compounds other
32 than acids or alcohols.
33
34
35 Supporting Information
36
37 The Supporting Information is available free of charge at: https://pubs.acs.org/doi/???/???.
38
39
SI includes melting properties, detailed experimental results and chemical structures. Table S1:
40
41 melting properties. Tables S2: detailed experimental results. Figures S1-S2: chemical
42
43 structures.
44
45 Acknowledgments
46
47
48 This work was developed within the scope of the projects CICECO-Aveiro Institute of
49
Materials, UIDB/50011/2020 & UIDP/50011/2020, financed by national funds through the
50
51 Portuguese Foundation for Science and Technology/MCTES, and CIMO-Mountain Research
52
53 Center, UIDB/00690/2020, financed by national funds through the FCT/MEC and when
54
55 appropriate co-financed by FEDER under the PT2020 Partnership Agreement. L.P.S.
56 acknowledges FCT for her PhD grant (SFRH/BD/135976/2018).
57
58
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